It is now possible to isolate genes and understand disease mechanisms in terms of the underlying molecular derangements. This knowledge is essential to develop and test protein, somatic cell gene, and stem cell therapies for human genetic diseases. The full scope of understanding the pathogenesis of these disorders and testing therapy cannot be realized without authentic (gene-homologous, orthologous) animal models for the studies that are not possible for ethical and practical reasons in human patients. Gene knockout technology in mice has provided a valuable source, but additional models are needed for studies requiring long-lived animals of larger size and diverse genetic background to be able to monitor efficacy and safety long-term. A reservoir of such diseases is present in existing dog and cat breeds that are relatively inbred but that retain genetic heterogeneity similar to that present in the Old Order Amish and Ashkenazi Jewish populations. The objective of this grant is to continue to serve as a National and International Referral Center to identify, characterize, verify, preserve, and make available for research new and existing large animal models of human genetic disease. These models involve defects in homologous gene loci having the same molecular and clinical phenotypes as in human patients. Models offering new opportunities to investigate disease pathogenesis and approaches to therapy will be emphasized in consultation with an Advisory Committee. The Center will provide the clinical, pathological, and molecular genetic studies required to discover important large animal models, including, as a new direction, those with complex inheritance, and establish their homology with the human disorder. Verified models will be made available to other investigators for a nominal fee-for-service in the form of DNA, cells, frozen semen, and breeding stock. We will also serve as a resource for normal dogs and cats and their tissues, and we will continue to offer a facility and expertise for investigators to perform pathogenetic and therapy experiments in dog and cat models on a Program Income Fund, fee-for-service basis.